The first year of human life is a period of significant maturation for both the lung and immune system. Infants are more susceptible to respiratory infections as compared to school age children and adults, but the immune mechanisms for this clinical observation are not well understood. The neonatal period of life is further challenged by reduced vaccine efficacy, which is in part due to developmental shifts in leukocyte function that limit establishment of protective immunity. It is currently unknown whether structural cells of the lung also contribute to the immunocompromised state of the infant. Of particular relevance is the role of the epithelial cell in conducting airways, which is architecturally and functionally poisedto serve as an innate immune liaison to the adaptive immune system. Given that mucosal surfaces serve as the first line of host defense, enhancement of innate immune function in airway epithelium may facilitate a more robust adaptive immune response towards infectious agents. The overall goal of our research is to understand the molecular mechanisms that program innate immune function in airway epithelial cells of the postnatal lung. In a pediatric model of H1N1 influenza infection, we have observed persistent bronchiolitis and alveolitis in infant rhesus monkey airways despite viral clearance. Infant monkey airway epithelial cell cultures revealed a modulated innate immune phenotype following H1N1 infection, as compared with adult monkey airway epithelial cell cultures. We now provide data demonstrating that interleukin 22 receptor, alpha 1 (IL-22R1), is developmentally regulated in infant monkey airway epithelial cells in a histone deacetylase dependent fashion. Given our published and preliminary findings, we hypothesize that limited host pathogen defense in the infant is mediated, in part, by modulated innate immune pathways in the airway epithelium. We further propose that the regulation of modulated innate immune pathways in infant airway epithelium is dependent upon epigenetic mechanisms. To test our hypothesis, we will use both in vitro and in vivo strategies in the context of H1N1 infection to (1) define the continuum of the infant airway epithelium transcriptome relative to adult airway epithelium in the context of viral infection; (2) investigat the epigenetic mechanisms that regulate IL-22R1 in the infant airway epithelium; (3) determine if epigenetic inhibitors can enhance mucosal immunity in infant airways. The rationale for proposing these exploratory studies under the R21 mechanism is to provide the foundation for the development of new adjuvant strategies for host defense directed at pediatric airway epithelium, by targeting specific molecules associated with innate immune pathways. While it is understood that airway epithelium has multiple pattern recognition receptors to recognize a diverse array of pathogens, here we will focus on influenza as a paradigm for respiratory infections.